Kinesin Kif3b mutation reduces NMDAR subunit NR 2A trafficking and causes schizophrenia‐like phenotypes in mice

Abstract

The transport of N ‐methyl‐ d ‐aspartate receptors ( NMDAR s) is crucial for neuronal plasticity and synapse formation. Here, we show that KIF 3B, a member of the kinesin superfamily proteins ( KIF s), supports the transport of vesicles simultaneously containing NMDAR subunit 2A ( NR 2A) and the adenomatous polyposis coli ( APC ) complex. Kif3b +/− neurons exhibited a reduction in dendritic levels of both NR 2A and NR 2B due to the impaired transport of NR 2A and increased degradation of NR 2B. In Kif3b +/− hippocampal slices, electrophysiological NMDAR response was found decreased and synaptic plasticity was disrupted, which corresponded to a common feature of schizophrenia ( SCZ ). The histological features of Kif3b +/− mouse brain also mimicked SCZ features, and Kif3b +/− mice exhibited behavioral defects in prepulse inhibition ( PPI ), social interest, and cognitive flexibility. Indeed, a mutation of KIF 3B was specifically identified in human SCZ patients, which was revealed to be functionally defective in a rescue experiment. Therefore, we propose that KIF 3B transports NR 2A/ APC complex and that its dysfunction is responsible for SCZ pathogenesis.